Using ketamine to test new drug therapies for schizophrenia

Schizophrenia is treated with drugs that block the chemical dopamine from sending signals in the brain.

Dopamine is a chemical messenger and is involved in reward, attention and movement, among other crucial bodily and cognitive functions. Blocking or inhibiting its action can cause unpleasant side effects and these drugs are not effective for all patients.

Long-standing evidence shows that another key chemical messenger in the brain, glutamate, is also involved in schizophrenia. Glutamate generally increases brain cell activity, and its effects can be amplified or reduced by dopamine. Research supported by the MRC and National Institute for Health Research (NIHR) Maudsley Biomedical Research Centre found that glutamate levels are higher in patients with more severe symptoms of schizophrenia, including those not responding to treatment.

Mimicking schizophrenia in healthy volunteers

New drug treatments are usually tested first in animals and then in patients, but many drugs fail this step. A safe intermediate test in healthy volunteers could provide important information that drugs are working, before moving to patients. Applying this approach to new schizophrenia drugs requires us to first mimic the disorder in healthy individuals.

Ketamine is an anaesthetic, but at low doses it alters glutamate functioning and causes reversible schizophrenia-like symptoms. We showed that changes in the brain induced by ketamine provide a powerful way of testing novel glutamate-targeted drug therapies for schizophrenia.

First, we used two doses of ketamine in healthy volunteers, and showed that our methods were safe, feasible and produced clear changes in brain function using brain scans. Using a dose of ketamine acceptable to volunteers we showed the methods worked with existing drugs that affect glutamate functioning. We also introduced new, more powerful methods for analysing large volumes of brain scanning data.

Testing novel targeted medicines

We then applied our methods to novel, glutamate-targeted medicines. With Eli Lilly, we tested two leading candidate medicines and identified doses which reduced the ketamine-induced brain changes and schizophrenia-like experiences.

This work represents a safe and valid tool that can ensure patients are exposed to only the most promising drugs and doses. We will now use our methods to understand how ketamine works in depression, with the aim of developing new drug treatments for those who do not benefit from other depression medications.

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